Design of Chalcones of 7-Azaindole as Raf-B Inhibitors

The present work deals with the design of 7-azaindole derivatives for its Raf-B inhibition. All the designed compounds follows Lipinski’s rule of five. In silico ADME predictions of all the designed compounds suggests that none of the compounds have problem with bioavailability. The compounds were designed on the binding affinity towards the Raf-B inhibition. It was observed that few of the designed compounds were found to have significant interaction with the active site of the receptor. The compounds possessing 3-hydroxyl-2-methyl as substitution in chalcone was found to possess maximum docking score than other designed compounds.

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Promising inhibitors against main protease of SARS CoV-2 from medicinal plants: In silico identification

Acta Pharmaceutica ◽

10.2478/acph-2022-0020 ◽

2021 ◽

Vol 72 (2) ◽

pp. 159-169

Author(s):

OLUWAKEMI EBENEZER ◽

MICHAEL SHAPI

Keyword(s):

Medicinal Plants ◽

Binding Affinity ◽

In Silico ◽

Complex Analysis ◽

Docking Studies ◽

Lipinski’S Rule ◽

Main Protease ◽

Pharmacokinetic Properties ◽

Lipinski’S Rule Of Five ◽

In Silico Identification

Abstract Some compounds reported as active against SARS CoV were selected, and docking studies were performed using the main protease of SARS CoV-2 as the receptor. The docked complex analysis shows that the ligands selectively bind with the target residues and binding affinity of amentoflavone (–10.1 kcal mol–1), isotheaflavin-3’-gallate (–9.8 kcal mol–1), tomentin A and D (–8.0 and –8.8 kcal mol–1), theaflavin-3,3’-digallate (–8.6 kcal mol–1), papyriflavonol A (–8.4 kcal mol–1), iguesterin (–8.0 kcal mol–1) and savinin (–8.3 kcal mol–1) were ranked above the binding affinity of the reference, co-crystal ligand, ML188, a furan-2-carboxamide-based compound. To pinpoint the drug-like compound among the top-ranked compounds, the Lipinski’s rule of five and pharmacokinetic properties of all the selected compounds were evaluated. The results detailed that savinin exhibits high gastrointestinal absorption and can penetrate through the blood-brain barrier. Also, modifying these natural scaffolds with excellent binding affinity may lead to discovering of anti-SARS CoV agents with promising safety profiles.

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Mengidentifikasi Peptida Bioaktif Angiotensin Converting Enzyme-inhibitor (ACEi) dari Kasein β Susu Kambing dengan Polimorfismenya Melalui Teknik In Silico

Jurnal Aplikasi Teknologi Pangan ◽

10.17728/jatp.3008 ◽

2019 ◽

Vol 7 (4) ◽

Author(s):

Hermawan Setyo Widodo ◽

Tridjoko Wisnu Murti ◽

Ali Agus ◽

Widodo Widodo

Keyword(s):

Angiotensin Converting Enzyme ◽

In Silico ◽

Digestive Enzymes ◽

Bioactive Peptides ◽

Enzyme Inhibitor ◽

Goat Milk ◽

Bioactive Peptide ◽

Converting Enzyme ◽

Lipinski’S Rule ◽

Lipinski’S Rule Of Five

Susu kambing memiliki komponen protein salah satunya protein β dan secara umum terjadi polimorfisme pada level protein. Perubahan urutan asam amino akibat polimorfisme memungkinkan adanya potensi dihasilkannya peptida bioaktif penghambat enzim pengubah angiotensin (ACEi). Penelitian ini bertujuan untuk menyaring peptida bioaktif yang berpotensi sebagai ACEi dari kasein β kambing beserta polimorfismenya. Penelitian ini dilakukan dengan teknik in silico terhadap sekuen kasein β kambing serta struktur tiga dimensi human testicular ACE. Langkah yang dilakukan dalam penelitian ini meliputi simulasi pemotongan peptida dengan enzim pencernaan (pepsin, tripsin dan kimotripsin), peninjauan karakteristik peptida lalu simulasi docking ligan-reseptor. Tampilan parameter Lipinski’s Rule of Five (Ro5), bioaktivitas dan energi afinitas dipertimbangkan untuk memilih peptida bioaktif. Hasil yang didapat menunjukkan bahwa ditemukan peptida bioaktif yakni INK (Ile-Asp-Lys) yang memiliki kemampuan hampir setara dengan lisinopril (afinitas energi -8,2kkal/mol vs. -8,3kkal/mol). Peptida INK dapat ditemukan dari hasil hidrolisis dari alel A, C, D dan E, sehingga polimorfisme tidak menyebabkan perbedaan produksi peptida bioaktif. Kesimpulan yang dapat diambil yakni kasein β susu kambing jika dicerna dengan enzim pencernaan dapat menghasilkan peptida bioaktif ACEi yakni INK.Identification of Angiotensin Converting Enzyme-inhibitor (ACEi) Bioactive Peptide from Goat Milk β-Casein with It's Polymorphism by In Silico TechniqueAbstractPolymorphism eventually may be occurred at the protein level. Changes in the amino acid sequence due to polymorphism may exhibit a potential action to generate of the angiotensin-converting enzyme inhibitors (ACEi) bioactive peptide. This study is aimed to assess bioactive peptides that have a great potent value as ACEi from goat β casein along with its polymorphism. The research was done by in silico technique on goat β-casein sequence and three-dimensional structure human testicular ACE. Peptide-cutting simulations with digestive enzymes (pepsin, trypsin and chymotrypsin), peptide properties review, then ligand-receptor docking simulations was applied in this research. Appearance of Lipinski's Rule of Five (Ro5), bioactivity and affinity energy were considered for selecting bioactive peptides. The results show that bioactive peptide found as INK (Ile-Asp-Lys) which had similar ability as lisinopril (energy affinity –8.2kcal/mol vs. –8.3kcal/mol). The INK peptides could be found from the hydrolysis resulted in alleles A, C, D and E, therefore polymorphism did not affect the differences of production of bioactive peptides. A conclusion, processed goat milk β casein with digestive enzymes could produce ACEi of INK as bioactive peptide.

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Investigation of biological activities of Colocasia gigantea Hook.f. leaves and PASS prediction, in silico molecular docking with ADME/T analysis of its isolated bioactive compounds

10.1101/2020.05.18.101113 ◽

2020 ◽

Author(s):

Safaet Alam ◽

Nazim Uddin Emon ◽

Mohammad A. Rashid ◽

Mohammad Arman ◽

Mohammad Rashedul Haque

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

In Silico ◽

Castor Oil ◽

Biological Activities ◽

Kappa Opioid Receptor ◽

Soluble Extract ◽

Docking Score

AbstractBackgroundColocasia gigantea is locally named as kochu and also better known due to its various healing power. This research is to investigate the antidiarrheal, antimicrobial, and antioxidant possibilities of the methanol soluble extract of Colocasia gigantea.MethodsAntidiarrheal investigation was performed by using in vivo castor oil induced diarrheal method where as in vitro antimicrobial and antioxidant investigation have been implemented by disc diffusion and DPPH scavenging method respectively. Moreover, in silico studies were followed by molecular docking analysis of several secondary metabolites were appraised with Schrödinger-Maestro v 11.1.ResultsThe induction of plant extract (200 and 400 mg/kg, b.w, p.o), the castor oil mediated diarrhea has been minimized 19.05 % (p < 0.05) and 42.86 % (p < 0.001) respectively. The methanolic extract of C. gigantea showed mild sensitivity against almost all the tested strains but it shows high consistency of phenolic content and furthermore yielded 67.68 μg/mL of IC50 value in the DPPH test. The higher and lower binding affinity was shown in beta-amyrin and monoglyceryl stearic acid against the kappa-opioid receptor (PDB ID: 4DJH) with a docking score of -3.28 kcal/mol and -6.64 kcal/mol respectively. In the antimicrobial investigation, Penduletin and Beta-Amyrin showed the highest and lowest binding affinity against the selected receptors with the docking score of -8.27 kcal/mol and -1.66 kcal/mol respectively.ConclusionThe results of our scientific research reflect that the methanol soluble extract of C. gigantea is safe which may provide possibilities of alleviation of diarrhea and as a potential wellspring of antioxidants which can be considered as an alternate source for exploration of new medicinal products.

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In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA dependent RNA polymerase (RdRp) and Necessary Proteases

10.26434/chemrxiv.12200495 ◽

2020 ◽

Cited By ~ 1

Author(s):

Trinath Chowdhury ◽

Gourisankar Roymahapatra ◽

Santi M Mandal

Keyword(s):

Rna Polymerase ◽

Active Site ◽

In Silico ◽

Significant Interaction ◽

Rna Dependent Rna Polymerase ◽

Docking Analysis ◽

Replicase Protein ◽

Arsenical Compounds ◽

Viral Replicase ◽

In Silico Identification

The work demonstrate screening of several arsenical compounds against RdRp of coronavirus. The study implies out of all arsenical compounds, darinaparsin shows its most effective results based on in silico docking analysis. This study also confirmed the significant interaction between the active site of viral replicase protein, endoribonuclease protein and different proteases with darinaparsin.

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In silico insight into the inhibitory effects of active antidiabetic compounds from medicinal plants against SARS-CoV-2 replication and posttranslational modification

Coronaviruses ◽

10.2174/2666796702666210118154948 ◽

2021 ◽

Vol 02 ◽

Author(s):

Habibu Tijjani ◽

Adamu Idris Matinja ◽

Ahmed Olatunde ◽

Maryam Haladu Zangoma ◽

Abubakar Mohammed ◽

...

Keyword(s):

Medicinal Plants ◽

In Silico ◽

Experimental Studies ◽

Inhibitory Effects ◽

Post Translational Modifications ◽

Lipinski’S Rule ◽

In Silico Studies ◽

Lipinski’S Rule Of Five ◽

Mutation Assay ◽

Insight Into

Background: The recent reemergence of the coronavirus (COVID-19) caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has prompted for the search of effective treatments in forms of drugs and vaccines. Aim: In this regards, we performed an in silico studies of 39 active antidiabetic compounds from medicinal plants to provide insight into their possible inhibitory potentials against SARS-CoV-2 replications and post-translational modifications. Top 12 active antidiabetic compounds with potential for dual inhibition of the replications and post-translational modifications of SARS-CoV-2 were analyzed. Results: Boswellic acids, celastrol, rutin, sanguinarine, silymarin and withanolides expressed binding energy for 3- chymotrypsin-like protease (3CLpro) (-8.0 to -8.9 Kcal/mol), papain-like protease (PLpro) (-9.1 to -10.2 Kcal/mol) and RNA-dependent RNA polymerase (RdRp) (-8.5 to -9.1 Kcal/mol) which were higher than that of the reference drugs (Lopinavir and Remdesivir) used in this study. Sanguinarine, silymarin and withanolides are most drugable phytochemicals among the other following phytochemicals as they obey the Lipinski’s rule of five analyses. Sanguinarine, silymarin and withanolides express moderately soluble with no hepatotoxicity, while silymarin and withanolides cannot permeate the blood-brain barrier and showed no Salmonella typhimurium reverse mutation assay (AMES) toxicity, unlike sanguinarine from the predictive absorption, distribution, metabolism, elimination, and toxicity (ADMET) studies. Conclusion: Sanguinarine, silymarin and withanolides could be proposed for further experimental studies for their development as possible phytotherapy for the COVID-19 pandemic.

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In Silico ADME/T Properties of Quinine Derivatives using SwissADME and pkCSM Webservers

International Journal of TROPICAL DISEASE & Health ◽

10.9734/ijtdh/2021/v42i1130492 ◽

2021 ◽

pp. 1-12

Author(s):

Jean Gonfi M. Mvondo ◽

Aristote Matondo ◽

Dani T. Mawete ◽

Sylvie-Mireille N. Bambi ◽

Blaise M. Mbala ◽

...

Keyword(s):

Physicochemical Properties ◽

In Silico ◽

Pharmacokinetic Profile ◽

Drug Formulation ◽

New Drugs ◽

Oral Drug ◽

Free Access ◽

Lipinski’S Rule ◽

Development Of Resistance ◽

Lipinski’S Rule Of Five

Aim: Malaria is among the most devastating and widespread tropical parasitic diseases. To overcome antimalarial drug resistance, new drugs need to be developed. This study is designed to establish the pharmacokinetic profile and toxicity of nine quinine derivatives as potential antimalarial drugs using in silico approaches by SwissADME and pkCSM. Methodology: The structures of investigated compounds were translated into canonical SMILES format and then submitted to SwissADME web tool that gives free access to physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness of compounds, and pkCSM webserver for predicting and optimizing pharmacokinetic and toxicity properties. Results: SwissADME mainly used to predict the physicochemical properties of compounds and their drug-likeness revealed that all quinine derivatives have good bioavailability and satisfied the Lipinski’s rule of five. The pkCSM results on the absorption, distribution, metabolism, excretion and toxicity show that all investigated compounds have a good pharmacokinetic profile and they are safe since they belong to class 4 of the Globally Harmonized System (300 < Category 4 ≤ 2000 mg/kg/day). Conclusion: Drug-likeness and ADME/T predictions of nine investigated quinine derivatives revealed that they are good candidates to oral drug formulation and thus they can be used in a broader context of overcoming the development of resistance by Plasmodium protozoans against most of the drugs currently used to treat malaria. As future prospects, further studies on bioevaluation of compounds are needed to elucidate their potential pharmacological activities.

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Studi In Silico Senyawa 1,4-Naphthalenedione-2-Ethyl-3-Hydroxy sebagai Antiinflamasi dan Antikanker Payudara

ALCHEMY Jurnal Penelitian Kimia ◽

10.20961/alchemy.17.1.43979.83-95 ◽

2021 ◽

Vol 17 (1) ◽

pp. 83

Author(s):

Richa Mardianingrum ◽

Kamiel Roesman Bachtiar ◽

Susanti Susanti ◽

Aas Nuraisah Aas Nuraisah ◽

Ruswanto Ruswanto

Keyword(s):

Breast Cancer ◽

Molecular Dynamics ◽

Molecular Docking ◽

In Silico ◽

The Body ◽

Dynamics Simulation ◽

Lipinski’S Rule ◽

Lipinski’S Rule Of Five ◽

Anti Inflammatory ◽

Cox 1

Inflamasi merupakan suatu respon dari tubuh terhadap adanya cedera maupun infeksi yang ditandai dengan timbulnya kemerahan, demam, bengkak, nyeri dan hilangnya fungsi. Inflamasi berkontribusi terhadap ketidakseimbangan sekresi sitokin yang akan menghambat terjadinya apoptosis pada sel kanker sehingga menyebabkan hiperproliferasi sel. Kanker payudara merupakan salah satu penyakit kanker dengan prevalensi tertinggi di urutan ke dua di dunia. Penelitian terdahulu melaporkan pemberian minyak atsiri rimpang bangle (Zingiber purpureum Roxb.) secara topikal mampu memberikan penghambatan inflamasi yang lebih tinggi daripada triamcinolone, namun spesifik senyawa yang berpotensinya belum diketahui. Tujuan dari penelitian ini, yakni mencari senyawa aktif hasil analisis GCMS minyak atsiri rimpang bangle yang berpotensi sebagai antiinflamasi dan antikanker payudara secara in silico. Metode yang digunakan berupa screening Lipinski’s rule of Five, farmakokinetika dan toksisitas senyawa hasil analisis GC-MS, serta penambatan molekul dan dinamika molekular. Hasil screening dan simulasi penambatan molekul menunjukkan bahwa senyawa 1,4-naphthalenedione-2-ethyl-3-hydroxy dapat berikatan dengan reseptor COX-1 (antiinflamasi), dan hERα (antikanker payudara), namun lebih selektif terhadap reseptor COX-1 dengan nilai energi bebas (ΔG) yang lebih kecil yakni sebesar -7,20 kkal/mol, dibandingkan dengan interaksinya terhadap reseptor Erα yang bernilai -6,00 kkal/mol. Hasil simulasi dinamika molekular menggunakan metode kalkulasi MM-GBSA menunjukkan bahwa kompleks (1,4-naphthalenedione-2-ethyl-3-hydroxy)-(COX-1) memiliki nilai ∆GTOTAL sebesar -24,22 kkal/mol. Nilai ini lebih kecil dibandingkan dengan ∆GTOTAL kompleks (1,4-naphthalenedione-2-ethyl-3-hydroxy)-(hErα) sebesar -8,92 kkal/mol). Hal ini menunjukkan bahwa tingkat afinitas 1,4-naphthalenedione-2-ethyl-3-hydroxy terhadap COX-1 diprediksi lebih baik dan lebih poten sebagai antiinflamasi dibandingkan sebagai antikanker payudara.In Silico Study of 1,4-Naphthalenedione-2-Ethyl-3-Hydroxy Compounds as Anti-inflamation dan Breast Anticancer. Inflammation is a response from the body to injury or infection which is characterized by redness, fever, swelling, pain, and loss of function. Inflammation contributes to the imbalance of cytokine secretion which will inhibit apoptosis in cancer cells, causing cell hyperproliferation. Breast cancer is one of the cancer diseases with the second-highest prevalence in the world. The pioneering works reported that topical application of Bangle (Zingiber purpureum R) was able to provide a higher inhibition of inflammation than triamcinolone, however, the specific potential of the compound was unknown. The purpose of this study is to find active compounds that have the potential to be anti-inflammatory and anti-cancer in the breast using in silico approach. The methods used are screening Lipinski’s Rule of Five, pharmacokinetics and toxicity of compounds from GC-MS analysis and molecular docking, and molecular dynamics. The screening and molecular docking simulation results showed that the compound 1,4-naphthalenedione-2-ethyl-3-hydroxy can bind to COX-1 (anti-inflammatory), and ERα (Estrogen Reseptor α), but was more selective towards COX-1 receptor with a binding affinity (ΔG) -7.20 kcal/mol, compare to its interaction with ERα which is -6.00 kcal/mol. The results of molecular dynamics simulation using the MM-GBSA calculation method show that the complex (1,4-naphthalenedione-2-ethyl-3-hydroxy)-(COX-1) has a value of ∆GTOTAL of -24.22 kcal/mol). This value is smaller than ∆GTOTAL of the complex (1,4-naphthalenedione-2-ethyl-3-hydroxy)-(hErα) of -8.92 kcal/mol. The results indicate that the affinity level of 1,4-naphthalenedione-2-ethyl-3-hydroxy to COX-1 was predicted to be better and more potent as an anti-inflammatory than as an anti-breast cancer.

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PENAPISAN MOLEKULAR KANDIDAT OBAT SINTETIK TUBERKULOSIS TERHADAP PROTEIN TIROSIN KINASE Mycobacterium tuberculosis

Jurnal Farmamedika (Pharmamedica Journal) ◽

10.47219/ath.v5i2.104 ◽

2020 ◽

Vol 5 (2) ◽

pp. 60-69

Author(s):

Harry Noviardi ◽

◽

Eem Masaenah ◽

Rizky Ramadhan

Keyword(s):

Mycobacterium Tuberculosis ◽

Binding Affinity ◽

Lipinski’S Rule ◽

Lipinski’S Rule Of Five

Mycobacterium tuberculosis (Mtb) merupakan bakteri penyebab infeksi pada penyakit Tuberkulosis (TB). Sebagian besar obat TB yang dikembangkan pada saat ini mulai dilakukan sejak 40 tahun lalu. Obat tersebut memungkinkan terjadinya resistensi terhadap Mycobacterium tuberculosis. Oleh karena itu perlu dikembangkan obat baru yang dapat mengobati TB. Protein tirosin kinase dapat dijadikan target pengobatan TB karena memainkan peran kunci dalam fisiologi Mycobacterium tuberculosis dan patogenesis. Pada penelitian ini dilakukan analisis efektifitas dari senyawa-senyawa turunan sintetik sebagai inhibitor pada penambatan molekular terhadap protein tirosin kinase yang berperan penting pada penyakit tuberculosis. Senyawa turunan sintetik dilakukan analisis penambatan molecular. Penentuan nilai konstanta inhibisi serta visualisasi interaksi obat dilakukan menggunakan Pymol dan Discovery Visualizer. Aktivitas farmakologi atau biologi senyawa ligan ditentukan berdasarkan kriteria Lipinski’s Rule of Five. Analisis toksisitas dengan menggunakan Toxtree dan admetSAR. Berdasarkan pada hasil penelitian diperoleh 5 kandidat senyawa potensial sebagai tuberkulosis, yaitu DC-159a, Delamid, BTZ-043, TBA-7371, dan PBTZ169 dengan nilai binding affinity berturut-turut -9,7; -9,6; -9,5; -9,4; dan -9,1 kkal/mol.Hasil analisis Lipinski menunjukkan bahwa semua senyawa tersebut memenuhi kriteria Lipinski. Sedangkan hasil uji toksisitas menunjukkan bahwa semua senyawa tersebut tidak berpotensi bersifat karsinogenik dan mutagenik

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Design and In silico Studies of 2,5-Disubstituted 1,2,4-Triazole and 1,3,4-Thiadiazole Derivatives as Pteridine Reductase 1 Inhibitors

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i29a31575 ◽

2021 ◽

pp. 166-178

Author(s):

Shraddha Phadke ◽

Devender Pathak ◽

Rakesh Somani

Keyword(s):

In Silico ◽

Therapeutic Potential ◽

Structural Features ◽

Lipinski’S Rule ◽

Drug Mechanism ◽

In Silico Studies ◽

Lipinski’S Rule Of Five ◽

Thiadiazole Derivatives

Aims: Design and in silico studies of 2,5-disubstituted triazole and thiadiazole derivatives as Pteridine Reductase 1 inhibitors. With a view to develop effective agents against Leishmaniasis, 2-substituted-5-[(1H-benzimidazol-2yl) methyl] azole derivatives (A1-A12) were designed against the target enzyme Pteridine reductase 1. Methodology: The series was designed by targeting Pteridine reductase 1 which is an enzyme responsible for folate and pterin metabolism. Based on thorough study of the enzyme structure and structural features of ligands required for optimum interaction with the enzyme, a series of 12 compounds consisting of 2,5-disubstituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives was designed. In silico studies were carried out which included docking studies (using V Life software) to understand binding of the compounds with enzyme PTR1, ADMET studies, drug likeness studies for physicochemical properties and bioactivity studies to understand the possible mechanism of action of the compounds. These studies were undertaken using online softwares, molinspiration and admetSAR web servers. Results: Compounds A10 and A12 gave the best docking scores of -59.9765 and -60.4373 respectively that were close to dihydrobiopterin (original substrate). All the compounds complied with Lipinski’s rule of five. Most of the compounds displayed favorable ADMET properties. Conclusion: The 2,5-disubstituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives exhibited good binding affinity for PTR1 enzyme (PDB code: 1E92). The docking scores indicated that enzyme binding may be governed by the nature and size of the substituents on the azole ring. The compounds display well-defined drug-like and pharmacokinetic properties based on Lipinski’s rule of five with additional physicochemical and ADMET parameters. Bioactivity studies suggested the possible drug mechanism as enzyme inhibition. Hence, this study provides evidence for consideration of valuable ligands in 2,5-disubstituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives as potential pteridine reductase 1 inhibitor and further in vitro and in vivo investigations may prove its therapeutic potential.

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